The goal of this research effort is to understand how an important type of white blood cell, called a T lymphocyte, recognizes the presence in the body of a microorganism or cancer cell. We are also examining how the T cell system avoids unwanted recognition of normal body components and what goes wrong with this control system in autoimmune disease. This research attempts to examine this question at the protein level, to provide a detailed understanding of how the substances making up these microorganisms or cancer cells (antigens) are made visible to the defending T cells. To accomplish these goals, we have examined the structure and function of special proteins termed major histocompatibility complex (MHC) molecules that are essential for antigens to be recognized by T cells and for these T cells to become active. In the past we have examined how differences among MHC molecules in different individuals affects the ability of these proteins to present antigen to T cells, the biochemistry of how MHC molecules interact with antigen, and the influence of the cellular environment on antigen interaction with MHC molecules. More recently, we have investigated the parts of MHC molecules involved in interaction with the primary HIV-1 receptor (the CD4 protein), a molecule that plays a critical role in allowing T cell immunity to develop, and the regions of MHC molecules that may interact with each other during the activation of T lymphocytes. Identification of these two sets of interaction regions on MHC molecules may allow the development of new drugs that can interfere with these events and modulate immunity, for example, in diseases such as multiple sclerosis.